Interest in amphetamine-like designer drugs has increased with the recent focus by the lay press on 3,4-methylenedioxymethamphetamine (MDMA; often referred to as "ecstasy"). Although this group of drugs has been available for a long time, the upsurge in its unauthorized use by psychotherapists and increasing use by the public for hedonistic purposes led to it being placed under Schedule 1 control recently by the Drug Enforcement Agency. Over the past 15 years, we have been actively investigating the effects of large toxicologic doses of methamphetamine on biogenic amine systems and more recently on neuropeptides. We have observed marked decreases in the activity of biosynthetic enzymes, concentrations of biogenic amines and their major metabolites, and in the density of receptors of these neurotransmitters in selected brain regions; moreover, alterations of substance P- and neurotensin-like immunoreactivity have been observed. Since MDMA is chemically similar to methamphetamine, we have recently studied its effects on these same parameters; in preliminary studies, we have observed alterations of brain tryptophan hydroxylase activity, concentration of 5-hydroxytryptamine, as well as in substance P- and neurotensin-like immunoreactivity similar to those observed after large doses of methamphetamine. We now propose to investigate thoroughly the effects of MDMA and other amphetamine-like designer drugs [3,4-methylenedioxyamphetamine (MDA), and 2,5-dimethyl-4-ethylamphetamine (DOET)] on the same neurochemical parameters, that are altered by methamphetamine. We are uniquely qualified to perform these studies since in the same animal we can measure biosynthesis, release and metabolism of biogenic amines. Moreover, we have recently acquired the autoradiographic techniques for measuring in situ receptor changes; furthermore, we have antisera which allow us to measure substance P and neurotensin concentrations by RIA analysis. With the use of these techniques, it is possible to gain significant insights into the effects, and subsequently the mechanism(s), by which these amphetamine-like designer drugs exert their effects. Not only will the results of these studies be important in understanding the effects and mechanism(s) of action of these abused drugs, but they could also provide valuable information on the interrelationships between the dopaminergic, serotonergic and peptidergic systems of the brain.